Transduction of Hematopoietic Stem Cells for Enhanced Immunotherapy of Melanoma

造血干细胞转导增强黑色素瘤免疫治疗

基本信息

批准号：
7782229
负责人：
Donald B Kohn
金额：
$ 29.49万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7782229
关键词：
Affect Autologous Avidity Biodistribution CD34 gene Cell surface Cells Clinical Clinical Trials Collaborations Complementary DNA Development Engineering Exclusion Experimental Models Genes Goals Hematopoietic Hematopoietic stem cells Human Human Engineering Image Immune system Immunologics Immunotherapy In Vitro Infusion procedures Kinetics Lead Lentivirus Vector Life Lymphopoiesis Malignant Neoplasms Mature T-Lymphocyte Melanoma Cell Methods Modality Modeling Mus Nerve Growth Factors Outcome Patients Peptides Performance Peripheral Blood Mononuclear Cell Peripheral Blood Stem Cell Phase I Clinical Trials Positron-Emission Tomography Pre-Clinical Model Process Production Proteins Public Health Relative (related person)Reporter Reporter Genes Role Safety Source Staging Stem cells Surface T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte Testing Time Transgenic Organisms Tumor Antigens V(D)J Recombination Variant abstracting base cancer cell cancer immunotherapy cancer therapy cell determination cellular engineering design effective therapy human embryonic stem cell human subject improved in vivo in vivo Model melanoma novel novel strategies peripheral blood programs receptor response stem tumor vector

项目摘要

PROJECT 3: TRANSDUCTION OF HEMATOPOIETIC STEM CELLS FOR ENHANCED IMMUNOTHERAPY OF MELANOMA. Project Leaders: Donald B. Kohn, James S. Economou, Antoni Ribas, Jerome A. Zack ABSTRACT Immunotherapy can be performed by expressing in T cells the genes encoding a T cell receptor (TCR) reactive against a tumor-associated antigen. This Project takes this approach, which is explored in Project 1, further by examining whether administration of hematopoietic stem cells (HSC) transduced with the genes encoding an anti-tumor TCR can lead to de novo production of T cells expressing the introduced TCR genes.. Theoretically, transduced HSC could serve as an additional long-term source of engineered T cells for sustained anti-tumor activity, to augment that of transduced mature T cells. We will develop and perform a Phase I clinical trial to assess the safety and feasibility of administering autologous CD34+ HSC transduced to express a TCR recognizing a peptide from MART-1 for immunotherapy of patients with advanced melanoma. These engineered CD34+ cells will be co-administered along with mature T cells transduced to express the same MART-1 TCR, but with a distinguishable reporter gene. This dual marking approach will allow identification, isolation and characterization of the TCR-expressing T cells produced in vivo from the CD34+ cells and determination of their in vivo biodistribution by using PET imaging. During the planning stage of the clinical trial, we will use pre-clinical models of human T cell production from HSC to perform detailed characterization of the T cells derived from transduced human HSC. Ongoing scientific collaborations will occur with all of the Projects and Cores of this Program. The clinical trial of this Project 3 will be performed in years 4-5 of this program, building on the clinical trial of Project 1 that defines the optimal methods for administration of the TCR-transduced T cells. These studies will assess the potential role of HSC for cancer immunotherapy using TCR-based approaches.

项目3：造血干细胞的转导为了增强黑色素瘤的免疫疗法。项目负责人：Donald B. Kohn，James S. Economou，Antoni Ribas，Jerome A. Zack 抽象的可以通过在T细胞中表达编码T细胞受体（TCR）的基因来进行免疫疗法反应针对肿瘤相关的抗原。该项目采用了该方法，该方法在项目1中进行了探讨进一步检查是否使用基因转导的造血干细胞（HSC）编码抗肿瘤TCR可以导致表达引入的TCR基因的T细胞的从头产生。从理论上讲，转导的HSC可以作为工程T细胞的附加长期来源持续的抗肿瘤活性，以增加转导的成熟T细胞的活性。我们将开发并执行 I期临床试验，以评估管理自体CD34+ HSC的安全性和可行性表达TCR识别来自MART-1的肽的TCR，以通过晚期黑色素瘤患者的免疫疗法。这些工程的CD34+细胞将与成熟的T细胞一起进行，以表达相同的mart-1 TCR，但具有可区分的记者基因。这种双重标记方法将允许从CD34+的体内产生的表达TCR的T细胞的鉴定，分离和表征细胞和通过使用PET成像来确定其体内生物分布。在计划阶段临床试验，我们将使用HSC的人类T细胞产生的临床前模型进行详细源自转导的人HSC的T细胞的表征。将进行持续的科学合作随着该计划的所有项目和核心。该项目3的临床试验将在几年内进行该计划的4-5，基于项目1的临床试验的基础，该试验定义了管理的最佳方法 TCR转导的T细胞的。这些研究将评估HSC对癌症免疫疗法的潜在作用使用基于TCR的方法。